CN101601617B - Intracranial paclitaxel medicament release stent and preparation method thereof - Google Patents
Intracranial paclitaxel medicament release stent and preparation method thereof Download PDFInfo
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- CN101601617B CN101601617B CN 200910088182 CN200910088182A CN101601617B CN 101601617 B CN101601617 B CN 101601617B CN 200910088182 CN200910088182 CN 200910088182 CN 200910088182 A CN200910088182 A CN 200910088182A CN 101601617 B CN101601617 B CN 101601617B
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Abstract
The invention relates to an intracranial paclitaxel medicament release stent and a preparation method thereof. The stent comprises a thin-wall hollowed ringer stent and a paclitaxel-containing degradable medicament coating coated on the stent, the stent consists of sine wave rods and connecting rods for connecting two adjacent sine wave rods, the sine wave rod consists of standard wave rods and deformation rods which are arranged at intervals, the standard wave rod consists of two straight rods and a circular arc connecting section, the rid width of the circular arc connecting section is smaller than the rid width of the straight rods, both the deformation rod and the connecting rod consist of two straight sections parallel to the straight rods of the standard wave rod and a bent connecting section for connecting the two straight sections, and the connecting rods are arranged on the deformation rod at intervals; and the coating comprising paclitaxel, degradable polymer and trichloroethane, acetone or tetrahydrofuran solvent on the tent layer upon layer respectively. The intracranial paclitaxel medicament release stent has even axial flexibility and low nominal pressure, effectively inhibits the neointimal formation of the blood vessel and the proliferation and migration of smooth muscle cells, and effectively solves the problem of intracranial arterial blood vessel restenosis.
Description
Technical field
The invention discloses a kind of balloon-expandable intracranial paclitaxel coating stent of medicine.
Background technology
Domestic expert studies show that the distribution that Chinese cerebral blood supply atherosclerotic is narrow is how common with intracranial.At present, for the narrow main Therapeutic Method of entocranial artery Drug therapy, the operation of surgery bypass graft and simple sacculus angioplasty etc. are arranged, but they all exist limitation separately, especially often curative effect is limited for serious narrow patient.
Now domesticly be specifically designed to the intracranial vessel support seldom, manyly clinically replace doing the narrow plasty of entocranial artery with coronary artery bracket.We know, coronary artery is more straight, and (Nominal Pressure) higher (greater than 6 atmospheric pressure) are pressed in soft section weak point of coronary artery bracket system and name, and intracranial vessel is tortuous, wall thin, replace doing the narrow plasty of entocranial artery with coronary artery bracket: the first, increased operating difficulty and risk; Second, use the bare bracket or the coating stent of medicine of can not degrading fully, complication such as the inflammation after can causing intracranial stent to be implanted, subacute and advanced thrombus, and entocranial artery vascular restenosis rate is up to 40%, and present support can not effectively address this problem.
A degradable medicaments support that is specifically designed to intracranial vessel becomes the drug stent of current urgent need.
Summary of the invention
It is even that the technical problem to be solved in the present invention provides a kind of axial compliance, intracranial paclitaxel (Paclitaxel) drug releasing stent that name is forced down, this support uses up the high-fall high-biocompatibility coating of separating as carrier controlled release taxol drug, effectively the formation of angiogenesis inhibiting inner membrance and the propagation and the migration of smooth muscle cell (SMC) also can effectively solve the problem of entocranial artery vascular restenosis.
Another technical problem that the present invention will solve provides the preparation method of above-mentioned intracranial paclitaxel drug releasing stent.
The present invention realizes by the following technical solutions:
A kind of intracranial paclitaxel drug releasing stent, it comprises the coating of degradable medicaments that contains paclitaxel that applies on thin wall hollow ferrule holder and the support, described support is made up of with the connecting rod that is connected two adjacent sinusoidal wave bars sinusoidal wave bar, this sine wave bar is by the standard wave bar of setting at interval and the crest that passes through circular arc linkage section and standard wave bar, the deformed rod that trough connects is formed, this standard wave bar is made up of two straight-bars and circular arc linkage section, the muscle of described circular arc linkage section is wide all wide less than the muscle of straight-bar, described deformed rod all is made up of with the bending linkage section that is connected two straight sections two straight sections that are parallel to standard wave bar straight-bar with connecting rod, the crest dislocation of the standard wave bar of adjacent sinusoidal wave bar is relative, and described connecting rod is disposed on the described deformed rod; Described coating of degradable medicaments is by 0～0.5 part by weight percentage: the solvent composition of the paclitaxel of 0.3～1.0 part ratio proportioning and polylactic acid and 20～40 parts.
Described solvent is trichloroethane, acetone or oxolane.
Described support adopts the L605 cobalt-base alloys.
The bending linkage section of described connecting rod is a S shape.
Described circular arc linkage section is approximate " Ω " shape bent angle structure.
The muscle wide region of described sinusoidal wave bar circular arc linkage section is 0.0660mm-0.0711mm, and straight-bar muscle wide region is 0.0787mm-0.0838mm, and the muscle wide region of connecting rod is 0.0635mm-0.0660mm.
Described each sinusoidal wave bar is provided with the crest of 2～3 standard wave bars.
A kind of preparation method of above-mentioned intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use ethanol, isopropyl alcohol, sodium hydroxide, acetone, chloroform, pure water or injection water that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. be that 0.3～1.0 part of polylactic acid joins in 20～40 parts trichloroethane, acetone or the tetrahydrofuran solvent with parts by weight, at ambient temperature, with the jolting of vibration incubator to dissolve and be uniformly dispersed after solution;
2. according to the polylactic acid percentage by weight be 0～0.5 part: 0.3～1.0 part ratio is chosen paclitaxel;
3. above-mentioned 0～0.5 part paclitaxel is joined in the solution that 1. obtains, get coating solution;
4. choose the coating solution of 3 kinds of concentration of preparation according to above-mentioned steps, wherein have the paclitaxel in two parts to get 0 at most;
5. the coating solution layering with above-mentioned 3 kinds of concentration is coated in described rack surface, and high pure nitrogen solidifies synchronously, and pressure remains on 1.0～2.0Psi, reaches 90～120 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 15～35 ℃ the condition dry 12～24 hours in vacuum in-0.2～0Mpa, temperature, described intracranial paclitaxel drug releasing stent.
Medication coat can be the polymer that contains paclitaxel or derivatives thereof and anti-platelet drug and anti-inflammatory response medicine.
The present invention has the following advantages:
(1) considers that entocranial artery is tortuous, very thin particularity, the present invention adopts the L605 cobalt-base alloys as the rack platform material, carry out rack forming by tubing being carried out processing such as laser engraving cutting and electrochemical polish, its biocompatibility excellence, mechanical strength big (comparing) with traditional coronary artery bracket-316L, can accomplish that wall is thin, diameter is more tiny, submissive section longer, improve its flexibility and compliance, and (less than 6 atmospheric pressure) are forced down in name, before support discharges external diameter remain on 0.85mm following (support discharge before external diameter be meant that support is loaded in the external diameter of carrying on the sacculus, also be the external diameter before mounting system is implanted), can excessive damage and the extruding blood vessel, can make support well enter the intracranial lesion blood vessel, be convenient to doctor's operation, risk when reducing art.
(2) support of the present invention is taked non-wide lath type design:
1. the lath type design reduces the overall metal coverage rate of support, reduce to insert local inflammation reaction and damage behind the human body, the entocranial artery endotheliocyte can cover rack surface rapidly, thereby shorten arteria coronaria endothelium repair time to reduce the incidence rate of thrombosis, restenosis, subacute stent thrombosis and advanced thrombus, safety is improved.
2. the straight-bar muscle wide region of support sine wave is more greatly 0.0787mm-0.0838mm, improves radial support power and X ray development; And the muscle wide region of circular arc linkage section less be 0.0660mm-0.0711mm, with metal stresses and the deformation that reduces corner, the muscle of the wide more sinusoidal wave bar of muscle of connecting rod is wide littler, and the muscle wide region is 0.0635mm-0.0660mm, thereby reduces the occurrence probability that face coat strips off.
(3) the circular arc linkage section of support of the present invention adopts little " Ω " shape bent angle structure of radius of curvature:
1. reduce the metal stresses and the deformation of corner, obviously reduce the warpage pressure of sinusoidal wave bar, the rebound degree of this part is descended.
2. when carrying out support and carrying sacculus to press to hold assembling, support is more closely combined with carrying sacculus, be not easy to take place resilience, thereby obviously improve the support retentivity, in clinical manipulation, lower because of the not enough support that causes of the retentivity incidence rate that comes off, make sinusoidal wave bar have bigger warpage space simultaneously, have the littler external diameter (0.7mm-0.85mm) that passes through after support is pressed and held, obviously improve the trafficability characteristic of this support, make clinical manipulation more reliably convenient.
3. after the support expansion, " Ω " shape bent angle structure is fully opened, and makes two straight-bars of sinusoidal wave bar become 40 degree, one 50 degree angles, and from the radial support power of this support of mechanical structure increase, and support has bigger diameter Free up Memory.
(4) connecting rod of support of the present invention takes two Line Segment to cooperate the lath type design of the S shape bending segment with four circular arcs, its straightway increases the overall length of bending segment, reduce the axial stress of bending segment, and compression takes place or stretches in the curved portion of four circular arcs of S shape bending segment when support carries out bending and expansion, therefore the axial compliance of support is greatly improved, the adherent property of axial blood vessel and the vascular compliance of support have been improved simultaneously, the normal physiological of malleable blood vessel is not out of shape to make support, reduces the damage to blood vessel.
(5) steric configuration of support of the present invention take adjacent sinusoidal wave bar standard wave bar crest dislocation relatively and connecting rod be disposed on the deformed rod of sinusoidal wave bar, make support under the prerequisite that keeps longer connecting rod, make the arrangement of adjacent sinusoidal wave bar more tight, thereby it is more even that the rack space Metal Distribution is covered, be difficult for taking place prolapsing or the excessive phenomenon of local metal density after inserting human body because of the uneven speckle that causes of Metal Distribution, success rate of operation and restenosis incidence rate at a specified future date all are improved, in addition, even metal covers and makes this support satisfy the uniformity requirement of drug stent to drug distribution.
The crest of the standard wave bar of sinusoidal wave bar is 2-3, connecting rod is arranged on the deformed rod of two adjacent sinusoidal wave bars in the mode at " different in the same way angles and be spaced ", when further improving the space Metal Distribution, make the axial compliance of support more even, and support external diameter size is impartial, appearance is slick and sly no lofty, reduces the generation of " fish scale " and " perk " phenomenon.
(6) coating of the present invention adopts and degrades the high-biocompatibility coating fully as carrier controlled release taxol drug, the taxanes medicine is as immunosuppressant, can make the related apoptosis that causes restenosis, but various cells are not quite similar to the tolerance degree of paclitaxel: smooth muscle cell to paclitaxel than the endotheliocyte sensitivity, animal experiment shows, compare with the drug stent that does not have fine and close sustained release layer, drug stent of the present invention can continue to reduce new intima and form, prevent restenosis, do not influence simultaneously normal endothelialization process, avoided the risk of tardy property thrombosis, efficiently, low side effect, avirulence, the effect that also has cell proliferation, the effectively formation of angiogenesis inhibiting inner membrance and the propagation and the migration of smooth muscle cell (SMC), reduce the inflammation after intracranial stent is implanted, the restenosis of blood vessel can effectively be prevented and suppress to complication such as subacute and advanced thrombus.
(7) coating of the present invention adopts the carrier mechanism that polylactic acid is uploaded, fixed and discharge as medicine, polymer was degraded to water and carbon dioxide through 120 days left and right sides time in vivo, discharge fully through metabolism, stay in the body without any non-biological material finishing under the prerequisite of medicine controlled releasing, improve endothelium and repair speed, reduce support and implant the generation of complication such as back inflammation, subacute and advanced thrombus, improve cerebrovascular patient's survival rate and quality of life.
Description of drawings
Fig. 1 is the structural representation of intracranial stent of the present invention;
The specific embodiment
Embodiment 1
As shown in Figure 1, a kind of intracranial paclitaxel drug releasing stent, it comprises the coating of degradable medicaments that contains paclitaxel that applies on the thin wall hollow ferrule holder of L605 cobalt-base alloys and the support, described support is made up of with the connecting rod 2 that is connected two adjacent sinusoidal wave bars sinusoidal wave bar 1, this sine wave bar is by the standard wave bar that is provided with at interval and by the crest 4 of Ω shape bent angle structure 3 with the standard wave bar, the deformed rod 6 that trough 5 connects is formed, this standard wave bar is made up of with Ω shape bent angle structure 3 two straight-bars 7, the muscle of described Ω shape bent angle structure is wide all wide less than the muscle of straight-bar, described deformed rod 6 all is made up of with the S shape bending linkage section 9 that is connected two straight sections two straight sections 8 that are parallel to standard wave bar straight-bar with connecting rod 2, crest 4 dislocation of described adjacent standard wave bar relatively, described connecting rod 2 is disposed on the described deformed rod 6; Described coating of degradable medicaments is by being 0～0.5 part by weight percentage: the solvent composition of the paclitaxel of 0.3～1.0 part ratio proportioning and polylactic acid and 20～40 parts, described solvent is trichloroethane, acetone or oxolane.
The muscle of described sinusoidal wave bar circular arc linkage section is wide to be 0.0660mm, and the straight-bar muscle is wide to be 0.0787mm, and the muscle of connecting rod is wide to be 0.0635mm.
A kind of preparation method of intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use ethanol that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. by weight percentage 0 part: 0.3 part, 0.2 part: 0.5 part, 0.5 part: 3 ratios of 1.0 parts are prepared three parts of paclitaxels and polylactic acid respectively;
2. the polylactic acid of 0.3 part of parts by weight is added in 20 parts the trichloroethane (analytical pure alkane), be 30rpm/min in frequency at room temperature with the vibration incubator, jolting adds 0 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed under the condition of amplitude φ 24mm;
0.5 part of polylactic acid added in 20 parts the trichloroethane (analytical pure alkane), jolting at room temperature adds 0.20 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed;
1.0 parts of polylactic acid are added in 20 parts the trichloroethane (analytical pure alkane), jolting at room temperature adds 0.5 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed,
Get the coating solution of 3 kinds of concentration;
3. the coating solution layering of above-mentioned 3 kinds of concentration is coated in the integral surface of described support, high pure nitrogen solidifies synchronously, and pressure remains on 1.0Psi, reaches 90 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 15 ℃ the condition dry 24 hours in vacuum in-0.1Mpa, temperature, described intracranial paclitaxel drug releasing stent.
Embodiment 2
A kind of intracranial paclitaxel drug releasing stent, its difference from Example 1 are that the muscle of described sinusoidal wave bar circular arc linkage section is wide to be 0.0711mm, and the straight-bar muscle is wide to be 0.0838mm, and the muscle of connecting rod is wide to be 0.0660mm.
A kind of preparation method of intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use acetone that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. by weight percentage 0.1 part: 0.4 part, 0.3 part: 0.6 part, 0.4 part: 3 ratios of 0.8 part are prepared three parts of paclitaxels and polylactic acid respectively;
2. the polylactic acid of 0.4 part of parts by weight is added in 30 parts the acetone (analytical pure), be 80rpm/min in frequency at room temperature with the vibration incubator, jolting adds 0.1 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed under the condition of amplitude φ 25mm;
0.6 part of polylactic acid added in 20 parts the acetone (analytical pure), jolting at room temperature adds 0.3 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed:
0.8 part of polylactic acid added in 40 parts the acetone (analytical pure), jolting at room temperature adds 0.4 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed,
Get the coating solution of 3 kinds of concentration;
3. the coating solution layering of above-mentioned 3 kinds of concentration is coated in the integral surface of described support, high pure nitrogen solidifies synchronously, and pressure remains on 2.0Psi, reaches 120 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 35 ℃ the condition dry 12 hours in vacuum in-0.2Mpa, temperature, described intracranial paclitaxel drug releasing stent.
A kind of intracranial paclitaxel drug releasing stent, its difference from Example 1 be,
The muscle of described sinusoidal wave bar circular arc linkage section is wide to be 0.0661mm, and the straight-bar muscle is wide to be 0.0788mm, and the muscle of connecting rod is wide to be 0.0636mm.
A kind of preparation method of intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use isopropyl alcohol that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. by weight percentage 0 part: 0.4 part, 0 part: 0.6 part, 0.5 part: 3 ratios of 0.8 part are prepared three parts of paclitaxels and polylactic acid respectively;
2. in the oxolane (analytical pure) with 20 parts of 0.4 part of polylactic acid addings of parts by weight, be 50rpm/min in frequency at room temperature with the vibration incubator, jolting adds 0 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed under the condition of amplitude φ 40mm;
0.6 part of polylactic acid added in 30 parts the oxolane (analytical pure), jolting at room temperature adds 0 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed:
0.8 part of polylactic acid added in 40 parts the oxolane (analytical pure), jolting at room temperature adds 0.5 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed,
Get the coating solution of 3 kinds of concentration;
3. the coating solution layering of above-mentioned 3 kinds of concentration is coated in the integral surface of described support, high pure nitrogen solidifies synchronously, and pressure remains on 1.5Psi, reaches 100 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 26 ℃ the condition dry 18 hours in vacuum in-0.1Mpa, temperature, described intracranial paclitaxel drug releasing stent.
A kind of intracranial paclitaxel drug releasing stent, its difference from Example 1 are that the muscle wide region of described sinusoidal wave bar circular arc linkage section is 0.0667mm, and straight-bar muscle wide region is 0.0800mm, and the muscle wide region of connecting rod is 0.0650mm.
A kind of preparation method of intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use sodium hydroxide that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. by weight percentage 0.2 part: 1.0 parts, 0.5 part: 0.3 part, 0 part: 3 ratios of 0.8 part are prepared three parts of paclitaxels and polylactic acid respectively;
2. 1.0 parts of polylactic acid of parts by weight are added in 40 parts the trichloroethane (analytical pure), jolting at room temperature adds 0.2 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed;
0.3 part of polylactic acid added in 30 parts the trichloroethane (analytical pure), jolting at room temperature adds 0.5 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed:
0.8 part of polylactic acid added in 40 parts the trichloroethane (analytical pure), jolting at room temperature adds 0 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed,
Get the coating solution of 3 kinds of concentration;
3. the coating solution layering of above-mentioned 3 kinds of concentration is coated in the integral surface of described support, high pure nitrogen solidifies synchronously, and pressure remains on 1.7Psi, reaches 95 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 20 ℃ the condition dry 18 hours in vacuum in-0.15Mpa, temperature, described intracranial paclitaxel drug releasing stent.
Embodiment 5
A kind of intracranial paclitaxel drug releasing stent, its difference from Example 1 are that the muscle of described sinusoidal wave bar circular arc linkage section is wide to be 0.0670mm, and the straight-bar muscle is wide to be 0.0798mm, and the muscle of connecting rod is wide to be 0.0656mm.
A kind of preparation method of intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use acetone that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. by weight percentage 0.25 part: 0.4 part, 0.15 part: 0.3 part, 0.4 part: 3 ratios of 0.6 part are prepared three parts of paclitaxels and polylactic acid respectively;
2. 0.4 part of polylactic acid of parts by weight is added in 30 parts the trichloroethane, jolting at room temperature adds 0.25 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed;
0.3 part of polylactic acid added in 30 parts the trichloroethane, jolting at room temperature adds 0.15 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed:
0.6 part of polylactic acid added in 20 parts the trichloroethane, jolting at room temperature adds 0.4 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed,
Get the coating solution of 3 kinds of concentration;
3. the coating solution layering of above-mentioned 3 kinds of concentration is coated in the integral surface of described support, high pure nitrogen solidifies synchronously, and pressure remains on 1.5Psi, reaches 105 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 19 ℃ the condition dry 21 hours in vacuum in 0Mpa, temperature, described intracranial paclitaxel drug releasing stent.
Embodiment 6
A kind of intracranial paclitaxel drug releasing stent, its difference from Example 1 are that the muscle of described sinusoidal wave bar circular arc linkage section is wide to be 0.0700mm, and the straight-bar muscle is wide to be 0.0808mm, and the muscle of connecting rod is wide to be 0.0660mm.
A kind of preparation method of intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use chloroform that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. by weight percentage 0.45 part: 0.4 part, 0.1 part: 0.3 part, 0.4 part: 3 ratios of 1.0 parts are prepared three parts of paclitaxels and polylactic acid respectively;
2. 0.4 part of polylactic acid of parts by weight being added in 40 parts the oxolane, is 70rpm/min with vibrating incubator in frequency at room temperature, and jolting adds 0.45 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed under the condition of amplitude φ 44mm;
0.3 part of polylactic acid added in 30 parts the oxolane, jolting at room temperature adds 0.1 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed:
1.0 parts of polylactic acid are added in 20 parts the oxolane, jolting at room temperature adds 0.4 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed,
Get the coating solution of 3 kinds of concentration;
3. the coating solution layering of above-mentioned 3 kinds of concentration is coated in the integral surface of described support, high pure nitrogen solidifies synchronously, and pressure remains on 1.1Psi, reaches 98 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 30 ℃ the condition dry 14 hours in vacuum in-0.1Mpa, temperature, described intracranial paclitaxel drug releasing stent.
Embodiment 7
A kind of intracranial paclitaxel drug releasing stent, its difference from Example 1 are that the muscle wide region of described sinusoidal wave bar circular arc linkage section is 0.0710mm, and straight-bar muscle wide region is 0.0830mm, and the muscle wide region of connecting rod is 0.0656mm.
A kind of preparation method of intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use pure water that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. by weight percentage 0.35 part: 0.5 part, 0.05 part: 0.35 part, 0.45 part: 3 ratios of 0.4 part are prepared three parts of paclitaxels and polylactic acid respectively;
2. 0.5 part of polylactic acid of parts by weight is added in 40 parts the trichloroethane, jolting at room temperature adds 0.35 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed;
0.35 part of polylactic acid added in 30 parts the trichloroethane, jolting at room temperature adds 0.05 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed:
0.4 part of polylactic acid added in 20 parts the trichloroethane, jolting at room temperature adds 0.45 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed,
Get the coating solution of 3 kinds of concentration;
3. the coating solution layering of above-mentioned 3 kinds of concentration is coated in the integral surface of described support, high pure nitrogen solidifies synchronously, and pressure remains on 2.0Psi, reaches 110 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 25 ℃ the condition dry 15 hours in vacuum in-0.2Mpa, temperature, described intracranial paclitaxel drug releasing stent.
A kind of intracranial paclitaxel drug releasing stent, its difference from Example 1 are that the muscle wide region of described sinusoidal wave bar circular arc linkage section is 0.0709mm, and straight-bar muscle wide region is 0.0828mm, and the muscle wide region of connecting rod is 0.0650mm.
A kind of preparation method of intracranial paclitaxel drug releasing stent, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use or injection water are cleared up the thin wall hollow ferrule holder;
(3) coating:
1. by weight percentage 0 part: 0.5 part, 0.5 part: 0.35 part, 0.5 part: 3 ratios of 0.4 part are prepared three parts of paclitaxels and polylactic acid respectively;
2. 0.5 part of polylactic acid of parts by weight being added in 40 parts the acetone, is 40rpm/min with vibrating incubator in frequency at room temperature, and jolting adds 0 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed under the condition of amplitude φ 35mm;
0.35 part of polylactic acid added in 30 parts the acetone, jolting at room temperature adds 0.5 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed:
0.4 part of polylactic acid added in 20 parts the acetone, jolting at room temperature adds 0.5 part of paclitaxel and is made into a kind of coating solution after dissolve and be uniformly dispersed,
Get the coating solution of 3 kinds of concentration;
3. the coating solution layering of above-mentioned 3 kinds of concentration is coated in the integral surface of described support, high pure nitrogen solidifies synchronously, and pressure remains on 2.0Psi, reaches 120 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 32 ℃ the condition dry 17 hours in vacuum in-0.05Mpa, temperature, described intracranial paclitaxel drug releasing stent.
Embodiment 9
Present embodiment provides a kind of study on the efficiency method of intracranial paclitaxel drug releasing stent:
The study on the efficiency that the present invention promptly contains the intracranial coating stent of medicine of taxol drug is to carry out excessively pulling on the coronary artery model of pig.The main terminal point of research: 4 weeks were observed terminal point, by scanning electron microscopic observation tunica intima, endothelium coverage condition; Vascular morphology learn to be measured neointimal hyperplasia index (on the support between inner film thickness, support inner film thickness, new intima area).
Embodiment 10
Present embodiment provides intracranial drug stent release in vitro assay method of the present invention:
18 intracranial drug stents (3 of each testing time points) are placed brown test tube with ground stopper, add the 20ml simulated body fluid simultaneously (with phosphate-buffered salt a slice, be dissolved in the water for injection of 1L, add 0.5% sodium azide solution, cryopreservation gets final product at the bovine serum albumin that faces with preceding adding 4%), put into the constant temperature culture agitator at different time points, rotating speed 100 times/minute, amplitude 2cm, test temperature is 37 ± 2 ℃.At 6 hours, 24 hours, 3 days, 7 days, 14 days, carried out release test in 28 days.
Take out drug stent release time in accordance with regulations, with 20 minutes eluting of acetonitrile supersonic vibration, take out support, with acetonitrile flushing support and with flushing liquor to the 25ml volumetric flask to scale, filtrate is measured medicament contg with HPLC, calculates the ratio that the medicine that discharges accounts for original drug loading.
High-efficient liquid phase chromatogram condition:
Chromatographic column is C18 post (4.6mm * 15mm, 5 μ m)
Mobile phase: acetonitrile: methanol: water (30: 50: 25)
Column temperature: 55 ℃ are detected wavelength: 230nm sample size: 20 μ l flow velocity: 1.0ml/min.
Claims (7)
1. intracranial paclitaxel drug releasing stent, it is characterized in that, it comprises the coating of degradable medicaments that contains paclitaxel that applies on thin wall hollow ferrule holder and the support, described support is made up of with the connecting rod that is connected two adjacent sinusoidal wave bars sinusoidal wave bar, this sine wave bar is by the standard wave bar of setting at interval and the crest that passes through circular arc linkage section and standard wave bar, the deformed rod that trough connects is formed, this standard wave bar is made up of two straight-bars and circular arc linkage section, the muscle of described circular arc linkage section is wide all wide less than the muscle of straight-bar, described deformed rod all is made up of with the bending linkage section that is connected two straight sections two straight sections that are parallel to standard wave bar straight-bar with connecting rod, the crest dislocation of the standard wave bar of adjacent sinusoidal wave bar is relative, and described connecting rod is disposed on the described deformed rod; Described coating of degradable medicaments is by 0～0.5 part by weight percentage: the solvent composition of the paclitaxel of 0.3～1.0 part ratio proportioning and polylactic acid and 20～40 parts, described solvent is trichloroethane, acetone or oxolane.
2. a kind of intracranial paclitaxel drug releasing stent according to claim 1 is characterized in that, described support adopts the L605 cobalt-base alloys.
3. a kind of intracranial paclitaxel drug releasing stent according to claim 1 is characterized in that the bending linkage section of described connecting rod is a S shape.
4. a kind of intracranial paclitaxel drug releasing stent according to claim 1 is characterized in that, described circular arc linkage section is approximate " Ω " shape bent angle structure.
5. a kind of intracranial paclitaxel drug releasing stent according to claim 1, it is characterized in that, the muscle wide region of described sinusoidal wave bar circular arc linkage section is 0.0660mm-0.0711mm, straight-bar muscle wide region is 0.0787mm-0.0838mm, and the muscle wide region of connecting rod is 0.0635mm-0.0660mm.
6. a kind of intracranial paclitaxel drug releasing stent according to claim 1 is characterized in that described each sinusoidal wave bar is provided with the crest of 2～3 standard wave bars.
7. the preparation method of the described intracranial paclitaxel drug releasing stent of claim 1 is characterized in that, its production stage is as follows:
(1) with cochrome L605 tubing electrochemical polishing treatment after the laser engraving cutting, is prepared into the thin wall hollow ferrule holder;
(2) support is carried out pretreatment: use ethanol, isopropyl alcohol, sodium hydroxide, acetone, chloroform, pure water or injection water that the thin wall hollow ferrule holder is cleared up;
(3) coating:
1. be that 0.3～1.0 part of polylactic acid joins in 20～40 parts trichloroethane, acetone or the tetrahydrofuran solvent with parts by weight, at ambient temperature, with the jolting of vibration incubator to dissolve and be uniformly dispersed after solution;
2. according to the polylactic acid percentage by weight be 0～0.5 part: 0.3～1.0 part ratio is chosen paclitaxel;
3. selected paclitaxel is joined in the solution that 1. obtains, get coating solution;
4. choose the coating solution of 3 kinds of concentration of preparation according to above-mentioned steps, wherein have the paclitaxel in two parts to get 0 at most;
5. the coating solution layering with above-mentioned 3 kinds of concentration is coated in described rack surface, and high pure nitrogen solidifies synchronously, and pressure remains on 1.0～2.0Psi, reaches 90～120 μ g/cm up to drug loading
2
(4) with being placed in the vacuum drying oven of above-mentioned coating, be under 15～35 ℃ the condition dry 12～24 hours in vacuum in-0.2～0Mpa, temperature, described intracranial paclitaxel drug releasing stent.
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| US20170273810A1 (en) * | 2016-03-24 | 2017-09-28 | Covidien Lp | Vascular flow diversion |
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